Cancer still represents a major unmet medical need. Initial treatment of the disease is often surgery, radiation treatment or the combination, but recurrent (metastatic) disease is common. Chemotherapeutic treatments for most cancers are generally not curative, but only delay disease progression. Commonly, tumors and their metastases become refractory to chemotherapy, in an event known as development of multidrug resistance. In many cases, tumors are inherently resistant to some classes of chemotherapeutic agents [see DeVita V. T., Principles of Cancer Management: Chemotherapy. In: Cancer. Principles and Practice of Oncology. DeVita V. T. et al (eds.), 5th edition, Lippincott-Raven, Philadelphia, New York (1977), pp. 333-347; or Cleton, F. J., Chemotherapy: general aspects. In: Oxford Textbook of Oncology; Peckham, M., et al, Oxford University Press, Oxford, New York, Tokyo (1995), Vol. 1, pp. 445-453]. This is, for example, the case for lung tumors, especially non-small cell lung carcinoma, or also for epidermoid tumors, like epidermoid head and neck, especially mouth, tumors, or also for breast tumors. Other mechanisms why tumors are not treatable (are refractory to treatment) can be, for example, the presence of tubulin mutations or glutathione mediated mechanisms.
Intestinal, especially colorectal, cancer defines a special case of the unmet medical needs in cancer treatment. Initial treatment of the disease is often surgery, radiation treatment or the combination, but recurrent (metastatic) disease is common. First-line chemotherapeutic treatments for recurrent colorectal cancer include 5-fluorouracil. But this treatment provides at best delay of disease progression as the tumors usually become refractory to treatment. Chemotherapy of this refractory stage of disease involves other classical cytotoxic agents, but are all considered inadequate [see Cohen et al., Cancer of the colon. In: Cancer. Principles and Practice of Oncology; DeVita et al. (eds.), 5th edition, Lippincoft Raven. Philadelphia, New York 1997, pp. 1144-1197; or Rowinsky, Ann. Rev. Med. 48, 353-74 (1997)]. Also for cancer of the genitourinary tract, especially prostate cancer, a further unmet medical need, initial treatment is as mentioned above for colorectal cancer, showing similar problems. First-line chemotherapeutic treatment for recurrent prostate cancer includes anti-androgens, and the recurrence is frequently androgen-dependent. But this treatment provides only delay of disease progression as the tumors almost always become refractory to anti-androgens within 6 months to 2 years (hormone-refractory prostate tumors). Chemotherapy of this anti-androgen refractory stage of diseases involves mitoxantrone or other classical anticancer cytotoxic agents, but all are considered as inadequate [see Oesterling et al., Cancer of the prostate. In: Cancer. Principles and Practice of Oncology. DeVita, V. T., et al. (eds.), 5th edition, Lippincott-Raven, Philadelphia, New York 1997, pp 1322-86; Sternberg, Cancers of the genitourinary tract. In: Cavalli et al. (eds.), Textbook of Medical Oncology; or Roth, B. J., Semin. Oncol. 23(6 Suppl.14), 49-55 (1996)].
Among cytotoxic agents for the treatment of tumors, TAXOL.RTM. (paclitaxel), a microtubule stabilizing agent, has become a very important compound with a remarkable economic success [see Rowinsky E. K., The development and clinical utility of the taxane class of antimicrotubule chemotherapy agents; Ann. Rev. Med. 48 353-374 (1997)].
However, TAXOL.RTM. has a number of disadvantages. Especially its extremely low solubility in water represents a severe problem. It has become necessary to administer TAXOL.RTM. in a formulation with Cremophor EL.RTM. (polyoxyethylated castor oil; BASF, Ludwigshafen, Germany) which has severe side effects, causing inter alia allergic reactions that in one case even were reported to have led to the death of a patient. More severely, certain tumor types are known to be refractory to treatment with TAXOL.RTM. even when the drug is administered as front-line therapy, or the tumors develop resistance to TAXOL.RTM. after multiple cycles of exposure.
Although the taxane class of antimicrotubule anti-cancer agents has been hailed as the "perhaps most important addition to the chemotherapeutic armamentarium against cancer over the past several decades" [see Rowinsky E. K., Ann. Rev. Med. 48, 353-374 (1997)] and despite the commercial success of TAXOL.RTM., there remain limitations to TAXOL.RTM.'s efficacy. TAXOL.RTM. treatment is associated with a number of significant side effects and some major classes of solid tumors, namely colon and prostate, are poorly responsive to this compound (see Rowinsky E. K., loc. cit.). Specifically, as a single agent, TAXOL.RTM. has been considered to be poorly active clinically in colorectal, renal, prostatic, pancreatic, gastric and brain cancers [see Rowinsky E. K., loc. cit.; Bitton, R. J., et al., Drug Saf. 12, 196-208 (1995); or Arbuck, S. G., et al., J. Natl. Cancer Inst. Monogr. 15, 11-24 (1993)]. For example, the effectiveness of TAXOL.RTM. can be severely limited by acquired drug resistance mechanisms occurring via various mechanisms, such as overexpression of phosphoglycoproteins that function as drug effiux pumps.
Therefore, there exists an urgent need to find compounds and appropriate dosing regimens with these compounds expand the armamentarium of cancer treatment, especially in the majority of cases where treatment with taxanes and other anticancer compounds is not associated with long term survival.
The epothilones, especially epothilones A and B, represent a new class of microtubule stabilizing cytotoxic agents (see Gerth, K. et al., J. Antibiot. 49 560-3 (1996); or Hoefle et al., DE 41 38 042), e.g. with the formulae: ##STR1##
wherein R is hydrogen (epothilone A) or methyl (epothilone B).
These compounds have the following advantages:
(i) they show better water solubility than TAXOL.RTM. and are thus more appropriate for formulation; and PA1 (ii) they have, in cell culture experiments, been reported to be active also against the proliferation of cells that, due to the activity of the P-glycoprotein efflux pump which renders them multidrug resistant, show resistance to treatment with other chemotherapeutics, e.g. TAXOL.RTM. [see Bollag, D. M., et al., "Epothilones, a new class of microtubule-stabilizing agents with a Taxol-like mechanism of action", Cancer Research 55, 2325-33 (1995); and Bollag D. M., Exp. Opin. Invest. Drugs 6, 867-73 (1997)]; and PA1 (iii) despite apparently sharing the same, or a sterically proximal binding site on the microtobule, the epothilones have been shown to be active against a TAXOL.RTM.-resistant ovarian carcinoma cell line with an altered .beta.-tubulin [see Kowalski, R. J., et al., J. Biol. Chem. 272(4), 2534-2541 (1997)]. PA1 a) a method of treatment (=for treating) of a proliferative disease, said method comprising the step of administering (for at least one treatment) an epothilone, especially epothilone A and/or B, especially B, (preferably in a pharmaceutically acceptable carrier material) to a warm-blooded animal, especially a human, in need of such treatment, in a dose that allows for the treatment of said disease (=a therapeutically effective amount), preferably in a dose (amount) as specified to be preferred hereinabove and hereinbelow; PA1 b) the use of an epothilone, preferably epothilone A and/or B, especially epothilone B, for the treatment of a proliferative disease; or an epothilone, especially epothilone B, for use in said treatment (especially in a human); PA1 c) the use of an epothilone, especially epothilone A and/or B, especially epothilone B, for the manufacture of a pharmaceutical preparation for the treatment of a proliferative disease; and/or PA1 d) a pharmaceutical preparation comprising a dose of an epothilone, especially epothilone A and/or B, most especially epothilone B, that is appropriate for the treatment of a proliferative disease; or any combination of a), b), c) and d), in accordance with the subject matter allowable for patenting in a country where this application is filed; PA1 e) a method of using an epothilone for the manufacture of a pharmaceutical preparation for the treatment of a proliferative disease, comprising admixing said epothilone with a pharmaceutically acceptable carrier. In cases where a tumor disease or a specific tumor (e.g. colon tumor, colon carcinoma or colon cancer; or prostate tumor, prostate carcinoma or prostate cancer) are mentioned instead of "proliferative disease", categories a) to e) are also encompassed, meaning that the respective tumor disease can be filled in under a) to e) above instead of "proliferative diseased", in accordance with the patentable subject matter. PA1 A dose of 1 mg/kg in mouse corresponds to a dose of 3 mg/m.sup.2 in a human. PA1 (A) Alkylating agents, preferably cross-linking chemotherapeutics, preferably bis-alkylating agents, PA1 (B) antitumor antibiotics, preferably doxorubicin (ADRIAMYCIN.RTM., RUBEX.RTM.); PA1 (C) antimetabolites; PA1 (D) plant alkaloids; PA1 (E) hormonal agents and antagonists, PA1 (F) biological response modifiers, preferably lymphokines or interferons PA1 (G) inhibitors of protein tyrosine kinases and/or serine/threonine kinases,; PA1 (H) antisense oligonucleotides or oligonucleotide derivatives; or PA1 (I) miscellaneous agents or agents with other or unknown mechanism of action. PA1 (a) at least one compound selected from epothilone A and (preferably) epothilone B and PA1 (b) at least one other chemotherapeutic agent PA1 (a) weekly in a human in a dose that lies between about 0.1 and about 6, preferably about 0.1 and about 5 mg/m.sup.2, more preferably about 0.1 and about 3 mg/m.sup.2, even more preferably about 0.1 and about 1.7 mg/m.sup.2, most preferably about 0.3 and about 1 mg/m.sup.2 ; or PA1 (b) three-weekly in a human in a dose that lies dose is between about 0.3 and about 18 mg/m.sup.2, preferably about 0.3 and about 15 mg/m.sup.2, more preferably about 0.3 and about 12 mg/m.sup.2, even more preferably about 0.3 and about 7.5 mg/m.sup.2, still more preferably about 0.3 and about 5 mg/m.sup.2, most preferably about 1.0 and about 3.0 mg/m.sup.2 ; PA1 (A) alkylating agents, preferably cross-linking chemotherapeutics, preferably bis-alkylating agents, PA1 (B) antitumor antibiotics, preferably doxorubicin (ADRIAMYCIN.RTM., RUBEX.RTM.); PA1 (C) antimetabolites; PA1 (D) plant alkaloids; PA1 (E) hormonal agents and antagonists, PA1 (F) biological response modifiers, preferably lymphokines or interferons PA1 (G) inhibitors of protein tyrosine kinases and/or serine/threonine kinases,; PA1 (H) antisense oligonucleotides or oligonucleotide derivatives; or PA1 (I) miscellaneous agents or agents with other or unknown mechanism of action; the combined treatment being timed so that component (a) and (b) are combined for simultaneous or chronologically staggered use within a period of time which is small enough for the active compounds both of component (a) and of component (b) to mutually enhance antiproliferative activity, e.g. in a patient.
On the other hand, they are highly toxic and therefore their usefulness in the treatment of cancer in vivo was considered practically impossible [see, for example, PNAS 95, 9642-7 (1998)]. Therefore, the present invention shows in an unexpected way that indeed dosage regimens may be found that allow, on the one hand, to treat tumors with epothilones, especially epothilone B; and on the other hand allow for the treatment of certain patient groups that are unresponsive to other kinds of treatment, be it by multi-drug resistance, as with taxane, e.g. TAXOL.RTM., refractoriness due to multidrug resistance, and/or any other mechanism.
The present invention has the goal to present for the first time in vivo regimens for a useful treatment with epothilones, preferably epothilone A or especially epothilone B, that allow for the treatment of a tumor disease, e.g. a melanoma, ovarian cancer, pancreas cancer, neuroblastoma, head and neck cancer, bladder cancer, renal, brain, gastric or preferably a colorectal, prostate, breast, lung (especially non-small cell lung) or epidermoid, e.g. epidermoid head and neck, especially mouth, cancer.
While the general treatment schedule allows for the treatment of various tumor types already in front-line treatment, the invention preferably relates to the treatment of tumors that can be expected or have shown to be refractory to treatment with other chemotherapeutics, e.g. standard treatment with one or more other chemotherapeutics, especially with 5-fluorouracil and/or taxane, e.g. TAXOL.RTM. treatment.
Surprisingly, it has now been found that even the proliferation of tumor cells and tumors that are refractory to standard treatment with other chemotherapeutics, e.g. 5-fluorouracil; and/or to treatment with a member of the taxane class of compounds, most especially TAXOL.RTM., especially of a colorectal tumor, especially one that is also refractory to standard treatment, e.g. with 5-fluorouracil; or of a lung tumor, especially a non-small cell lung cancer, an epidermoid, more preferably epidermoid head and neck, such as mouth, tumor; or a breast tumor; and/or metastasis thereof can be diminished or stopped and that even regression or tumor disappearance is possible.